Graft-versus-host disease (GVHD) is a common and serious complication after allogeneic hematopoietic cell transplantation (allo-HCT), while the closely related graft-versus-leukemia/lymphoma (GVL) effect is crucial for the effectiveness of allo-HCT for blood cancer patients. Adrenergic stress signaling mediated through ?- adrenergic receptor (AR) agonists such as norepinephrine is recognized to influence both innate and adaptive immunity. To investigate the previously unknown role of ?-AR signaling in GVHD, we used murine models to perform allo-HCT in which recipient mice were treated with specific ?-AR antagonists or agonists. Our findings show that agonistic stimulation of ?2-AR signaling significantly decreased GVHD while blocking of ?2-AR signaling significantly increased GVHD. We have also found that manipulating endogenous levels of norepinephrine, by exposing mice to a physiological stress (i.e. mild cold stress) completely recapitulates the findings obtained using pharmacologic manipulation of ?-AR signaling. Based on these findings, we hypothesize that stress-induced ?2-adrenergic signaling may control GVH and GVL responses via regulating the functions of donor-derived T cell subsets. Importantly, these findings suggest that manipulation of ?2-AR signaling is a feasible and immediately testable strategy to improve the effectiveness of allo-HCT. Therefore, we will study HCT patients and murine models to pursue three aims. Aim 1 will examine norepinephrine blood levels in allo-HCT patients as a potential factor influencing clinical outcomes. We will study about 200 de- identified patients to analyze the relationship between ?-adrenergic signaling levels and clinical outcomes including GVHD incidence, severity and cancer relapse. Aim 2 will evaluate the therapeutic potential of manipulating ?-AR signaling to modulate GVH and GVL responses. We have recently established a xenotransplantation system using humanized NSG mice as hosts to examine the GVH and GVL functions of human immune cells. We will use this new translational platform to evaluate the impact of manipulating ?-AR signaling on the GVH and GVL activities of human T cells. Aim 3 will explore T cell-dependent mechanisms by which ?2-AR signaling impacts GVH and GVL responses. We will use ?2-AR deficient mice as donors to determine how ?2-AR signaling affects the functions of major T cell subsets known to dictate the onset and severity of GVHD and to mediate the favorable GVL effect. In summary, this project will not only improve our understanding of the basic biology of allo-HCT, but it may also help to explain why patients, who naturally exhibit widely differing stress responses, differ so widely in terms of their development of GVHD or cancer remission. Moreover, this research may lead to a completely new therapeutic rationale based upon manipulation of ?-AR signaling for the prevention of GVHD and preservation of the beneficial GVL effect.